The leading cause of blindness in the United States is retinal degeneration, typically involving the death of photoreceptors (rods and cones). Retinitis pigmentosa (RP) refers to a major group of hereditary retinal degenerative diseases commonly caused by mutations in rod-specific genes. These genetic defects cause rods to die followed by gradual degeneration of normal cones. It is cone death that results in progressive vision loss in RP. RP affects over 100,000 people in the United States with no treatment or prevention currently available. Our long-term goal is to understand the mechanism of photoreceptor degeneration in RP and to develop therapies that save photoreceptors and restore visual function in RP patients. A major challenge to saving rods is the heterogeneous nature of RP, as many mutations have been identified in rod-specific genes; thus, each mutation may require a unique therapy. By contrast, saving cones may provide a more general means to save vision for RP. Our previous study demonstrated a novel role of HDAC4 in promoting rod survival in a mouse model of RP. We will expand our studies through the following Aims: Aim 1) we will investigate the molecular and cellular mechanisms through which HDAC4 protects photoreceptors in retinal degeneration mice. Using a cre-loxp system to restrict HDAC4 expression in specific cell types, we will test whether HDAC4 exerts its pro-survival effect in photoreceptors through a cell-autonomous mechanism versus HDAC4's effect in other cell types. We will further test whether the HDAC4 deacetylase domain is required for its effect in photoreceptor protection. Aim 2) we will test whether HDAC4 saves photoreceptors in both fast and slower retinal degeneration models. Using AAV (adeno-associated virus)-mediated gene transfer in rd1 mice (a fast retinal degeneration model), we will test whether HDAC4 directly promotes cone survival. We will test for preserved cone structure and critical components in cone phototransduction. Using AAV-mediated gene transfer in VPP and rd10 mice (slower retinal degeneration models), we will investigate 1) whether photoreceptor protection requires developmental expression of HDAC4; 2) whether HDAC4 can be used as a more general survival factor for photoreceptor protection. Aim 3) we will investigate major survival signaling pathways that are inactivated during retinal degeneration and reactivated in HDAC4-saved cones. We will further test whether HDAC4-saved cones restore visual function using: 1) electrophysiology to test the integrity of neural circuits in the retina and visual cortex; 2) behavioral tests to determine whether rescued retinal function can guide complex behaviors. In summary, our proposed studies will elucidate the molecular and cellular mechanisms and pathways through which HDAC4 promotes the survival of photoreceptors, the main target of genetic diseases in the retina. Our proposed research on the pro-survival effect of HDAC4 in both rods and cones will advance the therapeutic paradigm for a major group of blinding diseases. PUBLIC HEALTH RELEVANCE: We propose to utilize the pro-survival effect of HDAC4 (histone deacetylase 4) to protect retinal neurons in retinal degenerative diseases that cause progressive vision loss in humans. Understanding the mechanisms by which HDAD4 functions in the retina may lead to new therapeutic interventions for other degenerative diseases in the central nervous system, such as Alzheimer's disease, Huntington's disease, and spinocerebellar ataxia.